The triazole antifungal drug i.e., 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl) tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one is commonly known as posaconazole, an antifungal agent which is used against a wide range of fungal pathogens, including both yeast and molds.
U.S. Pat. No. 5,403,937 discloses a process for the preparation of key intermediate of posaconazole, specifically ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl-4-methylbenzenesulfonate. The process involves the usage of n-butyllithium during the preparation of oxazolidinone lithium salt, which is extremely flammable. The process requires column chromatographic purification at different stages to purify the intermediates which is tedious and lengthy process. The above said drawbacks make the process unviable on commercial scale.
In view of the above, there is an obvious need to find an efficient and industrially advantageous process for the synthesis of above said key intermediate of posaconazole which overcomes the problems associated with the prior art such as prolonged reaction time, low yields and tedious purifications.
U.S. Pat. No. 5,661,151 (hereinafter referred to as “151”) discloses several substituted tetrahydrofuran antifungal compounds, including posaconazole. This patent discloses several processes for the preparation of posaconazole.
According to one process, posaconazole is prepared by the condensation of toluene-4-sulfonic acid (−)-(5R-cis)-5-(2,4-difluorophenyl)-5-[1,2,4]triazol-1-ylmethyl tetrahydro-3-furanmethyl ester with N-protected triazolone derivative in the presence of a strong base in an aprotic solvent to give a compound, which is then deprotected using hydrochloric acid in methanol followed by N-alkylation with brosylated (2S,3R) alcohol in the presence of cesium carbonate in an aprotic solvent to give hydroxy protected posaconazole, and is then deprotected to give posaconazole.
The major drawback of the above said process is that, the N-alkylation is carried out on cyclized triazolone intermediate which requires excess amount of an expensive alkylating agent, and results in a mixture of N-alkylated and O-alkylated posaconazole, necessitating laborious purification methods such as column chromatography which is a time consuming and tedious process, especially for large quantities hence it is not suitable for large scale production and further results in low yields of posaconazole.
U.S. Pat. No. 5,625,064 discloses a process for the preparation of posaconazole which involves the condensation of 1-((2S,3R)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one with (−)-(5R-cis)-5-(2,4-difluorophenyl)-5-[1,2,4]triazol-1-ylmethyl-tetrahydro-3-furanmethylester derivative in the presence of a base to give benzyl ether of posaconazole which is then deprotected either with palladium on carbon in the presence of formic acid or aqueous hydrobromic acid to form posaconazole.
The above process suffers from several drawbacks such as low yield. It was observed that condensation of unprotected hydroxyl derivative with hydrazine derivative results in low yield of the compound. Further, condensation of O-benzyl protected phenyl carbamate derivative results in the formation of impurities which requires tedious purification processes hence results in low yield. In addition, the deprotection of benzyl ether of posaconazole in the presence of formic acid does not go to completion of the reaction or requires more than 30-35 hours. This may lead to degradation of final product and may require tedious purification processes such as chromatography purification or refluxing of the product with aqueous sodium hydroxide solution for another 24 hours as reported in the prior art. On the other hand, deprotection of benzyl ether of posaconazole with aqueous hydrobromic acid results in the degradation of compound of formula 1 and also requires laborious purification methods to purify posaconazole, hence results in the loss of yield and purity.
In view of the above, there is an obvious need to find an efficient and industrially advantageous process for the synthesis of posaconazole which overcomes the problems associated with the prior art such as prolonged reaction time, use of hazardous reagents, stringent reaction conditions, low yields and tedious purifications.
Three polymorphic forms of posaconazole designated as forms I, II and III are described and characterized in WO 99/18097 (U.S. Pat. Nos. 6,713,481, 6,958,337). Crystalline forms II and III were found to be unstable under the conditions investigated, so that crystalline form I was considered to be useful in the development of a pharmaceutical product.
Amorphous form of posaconazole produced as per the process disclosed in U.S. Pat. No. 5,661,151 by using 6N HCl in methanol is not stable. As of the date, there is no process available in the art for the preparation of stable amorphous posaconazole.
Hence there is a need to develop an alternative process for the preparation of amorphous form of posaconazole, which is more stable when used in a pharmaceutical composition and/or which have properties that make them suitable for bulk preparation and handling.
In view of the foregoing, there is an obvious need to find an efficient and industrially advantageous process for the synthesis of posaconazole and its intermediates as well as novel polymorphic forms of said compounds, which overcomes the problems associated with the prior art such as prolonged reaction time, use of hazardous reagents, stringent reaction conditions, low yields and tedious purifications.